Pharmaceutically active composition containing artemisinine and/or derivative of artemisinine

ABSTRACT

The invention relates to a pharmaceutically active composition containing a substance which is active against malaria parasites and shows a high level of activity against multiresistant lines of  Plasmodium falciparum.  The inventive composition is characterized in that it contains the active agent artemisinine and/or a derivative of artemisinine in a carrier material which is inert with the active agent, in a pharmaceutically active quantity and in that the carrier material is essentially free of compounds with a hydrophilic-lipophilic balance between 7 and 9.9.

The present invention relates to a pharmaceutically active compositionwhich contains a substance active against malaria parasites and has ahigh activity against multiresistant lines of Plasmodium falciparum. Thepresent invention relates in particular to an acceptable form ofartemisinin and/or a derivative of artemisinin, for example arteether,artemether, artemisin or artesunate, especially artesunate, for rectaladministration. Artesunate is a water-soluble derivative of artemisinin.Artemisinin (qinghaosu) is obtained from the leaves of the shrubArtemisia annua and is a naturally occurring sesquiterpene lactone withan endo peroxide group. Because of the low water solubility of thenatural substance artemisinin, attempts have been made to convert it toa variety of synthetic derivatives in order to improve thepharmaceutical availability. One such derivative is artesunate.Artemisinin and artesunate are efficient active substances in thetreatment of malaria. Artemisinin preparations are currently thesubstances which act most rapidly against malaria parasites. Inparticular, they show a high activity against multiresistant lines ofPlasmodium falciparum. Also, when administered to humans, only a fewside effects and no significant toxicity have been observed, althoughneurotoxicity has occurred in animals. Nevertheless, relatively littlehas hitherto been disclosed about the pharmacogenetics of artemisininand artesunate, which may be connected with the complicated analyticalmethods needed to quantify these drugs in the blood.

In the body, both artemisinin and artesunate are converted todihydroartemisinin (DHA, artesol), which is the actual schizonticidalactive substance. Artemisinin and artesunate can therefore be regardedas prodrugs for dihydroartemisinin.

Artesunate corresponds to the compound dihydroartemisinin hemisuccinateand its salts, especially its sodium salt. Dihydroartemisinin has thechemical name3α,12α-epoxy-3,4,5,5aα,6,7,8aα,9,10,12β,12a-dodecahydro-10-hydroxy-3β,6α,9β-trimethylpyrano[4,3-j]-1,2-benzodioxepine.Dihydroartemisinin is also known by the name dihydroqinghaosu.Artesunate, or dihydroartemisinin hemisuccinate, can be prepared forexample by converting dihydroartemisinin to dihydroartemisininhemisuccinate by means of acylation. Arteether, artemether and artemisinare known per se.

Artemisinin, artesunate, dihydroartemisinin and derivatives thereof aremanufactured especially in China and Vietnam and are marketed forexample in tablet form. In severe cases of malaria (possibly cerebral)caused by Plasmodium falciparum, the patients are often unconscious andan oral treatment is not possible. The parenteral administration ofquinine, for example, is only permitted in hospitals. In such casesartesunate in a rectal form of administration can save lives throughoutthe world and in practically any situation. A further advantage of therectal form is administration to children, where oral use is oftencomplicated by swallowing problems. Rectal forms of artesunate can alsobe administered successfully for other types of malaria, e.g. VIVAX.

Approximately one million children die of malaria every year in Africa.Although tablets and injectable solutions (as a powder preparation) arealready commercially available, suppositories are not. This isprincipally connected with the fact that artesunate is unstable inconventional suppository formulations, especially at elevatedtemperature. Numerous areas, for example subtropical and tropicalregions, often have an exceptionally warm climate and hence alsoabove-average temperatures. Furthermore, by their very nature,suppositories are generally unstable at elevated outside temperaturessince they are intended to melt at approx. 37° C.

The object of the present invention is to find a rectal pharmaceuticalform containing artemisinin and/or a derivative of artemisinin, forexample arteether, artemether, artemisin and/or artesunate, especiallyartesunate, as the active substance, this form having an adequatestability of the active substance for the appropriate storage period andcontaining a sufficient amount of active substance to allow reliablecontrol of the Plasmodium pathogens in the blood. Examples of rectalforms are suppositories, rectal foams, enemas or rectal capsules. Theterm artesunate will be used predominantly hereafter to representartemisinin and its derivatives.

The conventional prerequisite for the production of rectal capsules isthe presence in every case of surface-active substances, especiallywetting agents (surfactants), but also emulsifiers and optionallywashing-active substances, in order to assure an adequatebioavailability of the active substance by improving the distribution inthe rectum. However, studies have shown that such artesunateformulations have a high degree of instability even after a shortstorage period.

Surface-active substances are subdivided according to theirhydrophilic-lipophilic balance, i.e. by means of their HLB values, intoantifoams (HLB values of 1-3), emulsifiers (HLB values of 4-6 and 8-18),wetting agents (HLB values of 7-9), washing-active substances (HLBvalues of 13-15) and solubilizers (HLB values of 10-18). The boundariesbetween these effects overlap partially and are fluid. Depending on thecomposition in which it is present, a compound may exhibit its assignedeffect inadequately, if at all, despite its HLB value, or it may act forexample both as an emulsifier and as a wetting agent. Compounds referredto as antifoams, emulsifiers, wetting agents, washing-active substancesand solubilizers are known per se.

It has now been found, surprisingly, that a composition which issubstantially free of compounds with an HLB value in the range 7-9.9,and which contains the active substance artemisinin and/or a derivativeof artemisinin, especially artesunate, in an excipient which is inerttowards the active substance, not only gives a medicinally stableformulation which satisfies the requisite criteria in respect of thechemical stability of the active substance, but also has an activesubstance bioavailability which is within the internationally recognizedlimits applied to comparative bioavailability.

In terms of the present invention, the expression “substantially free ofcompounds with an HLB value in the range 7-9.9” means that any compoundpresent with an HLB value in the range 7-9.9, preferably a compound withan HLB value in the range 7-9, has a concentration in the composition ofat most 10 percent by weight, preferably at most 5 percent by weight andparticularly preferably at most 2 percent by weight, based on the weightof the pharmaceutically active substance. It is usually preferred thatno compound with an HLB value in the range 7-9.9, preferably no compoundwith an HLB value in the range 7-9, be present in the composition.

The present invention is defined in the claims. In particular, theinvention relates to a pharmaceutically active composition whichcontains a substance active against malaria parasites and has a highactivity against multiresistant lines of Plasmodium falciparum,characterized in that this composition contains a pharmaceuticallyeffective amount of the active substance artemisinin and/or a derivativeof artemisinin in an excipient which is inert towards the activesubstance, and the excipient is substantially free of compounds with anHLB value in the range 7-9.9, preferably in the range 7-9.

The expression “artemisinin and derivatives of artemisinin” is to beunderstood as meaning especially arteether, artemether, artemisin and/orartesunate, preferably artesunate.

The present invention further relates to the use of the compositionaccording to the invention for the production of pharmaceutical formsfor rectal administration. Such forms for rectal administration arepreferably suppositories, rectal foams, enemas and rectal capsules.

The present invention further relates to rectal forms, preferablysuppositories, rectal foams, enemas or rectal capsules, particularlypreferably suppositories and rectal capsules, which contain acomposition according to the invention. Rectal capsules are preferred.

The present invention further relates to suppositories, characterized inthat they consist of a hard gelatin capsule or a soft gelatin capsulecontaining a pharmaceutically effective amount of the compositionaccording to the invention, the hard gelatin capsule or the soft gelatincapsule being provided with a lubricating coating consisting of coatingmaterials known per se for rectal capsules. Suppositories consisting ofa soft gelatin capsule are preferred. The present invention furtherrelates to the use of these suppositories for controlling malariaparasites and multiresistant lines of Plasmodium falciparum.

The composition according to the invention is preferably alsosubstantially free of compounds with an HLB value in the ranges 4-6.9and 10-13. In other words, any such compound present in the compositionhas a concentration of at most 10 percent by weight, preferably at most5 percent by weight and particularly preferably at most 2 percent byweight, based on the weight of the pharmaceutically active substance. Itis usually preferred that no compound with an HLB value in the ranges4-6 and 10-13, preferably in the ranges 4-6.9 and 10-13, be present inthe composition.

The composition according to the invention is preferably alsosubstantially free of compounds with an HLB value in the range 13.1-15.In other words, any such compound present in the composition has aconcentration of at most 10 percent by weight, preferably at most 5percent by weight and particularly preferably at most 2 percent byweight, based on the weight of the pharmaceutically active substance. Itis usually preferred that no compound with an HLB value in the range13-15, preferably in the range 13.1-15, be present in the composition.

Suppositories and rectal capsules are preferred. Suppositories areintended to melt at about 37° C. In hot countries where the averagetemperature is already 37° C. or above, rectal capsules are thereforeused, while in latitudes where the average temperatures are below 37°C., it is preferred to use suppositories.

Artesunate is dihydroartemisinin hemisuccinate (C₁₉H₂₈O₈) and has theformula

Wetting agents can be anionic, cationic, amphoteric or non-ionic.Conventional wetting agents have an HLB value of about 7-9 and are e.g.anionic wetting agents such as alkali metal or ammonium salts ofunsaturated fatty acids, especially alkali metal alkylsulfates, e.g.sodium dodecylsulfate, sodium laurylsulfate, sodium cetylstearylsulfateor sodium docosanoate, alkali metal and alkaline earth metal salts ofalkyl- or arylalkylsulfonates, salts of gallic-acid, such as sodiumcholate, and acidic saponins. Examples of cationic wetting agents arequaternary ammonium compounds. Examples of amphoteric wetting agents arelecithins and betaine derivatives. Examples of non-ionic wetting agentsare fatty alcohols, cholesterols, optionally in combination with primaryemulsifiers, e.g. emulsifying cetylstearyl alcohol (a combination ofsodium cetylstearylsulfate and cetylstearyl alcohol) or cetomacrogolemulsifying wax, cholesterol, partial fatty acid esters of glycerol,such as glycerol fatty acid monoesters, e.g. glycerol monostearate,optionally in combination with hydrophilic emulsifiers, partial fattyacid esters of sorbitan, ethoxylated partial fatty acid esters ofsorbitan, other partial fatty acid esters, fatty acid esters ofpolyoxyethylene, fatty alcohol ethers of polyoxyethylene, fatty acidesters of sucrose, fatty acid esters of polyglycerol, and blockcopolymers of polyoxyethylene and polyoxypropylene. Such surfactants arenormally used in an amount of 1 to 10 percent, based on the fillingweight. According to the present invention, it is preferred not to usewetting agents.

Excipients which are inert towards the active substance are especiallywaxes, fats and oils, as well as mixtures thereof. These can be ofvegetable or animal origin and can also be hydrogenated. Waxes, fats andoils of vegetable origin are preferred. It is also possible to useparaffin waxes and paraffin oils.

Examples of waxes are natural plant waxes, such as carnauba wax, waxesof animal origin, such as yellow or white beeswax, and stearin waxeswith melting points (or melting point ranges) of between about 47° C.and about 88° C. However, it is also possible to use paraffin waxes, forexample hard paraffins with melting points of between about 47° C. andabout 65° C., and microcrystalline waxes with melting points of betweenabout 54° C. and about 105° C. Such waxes are used principally asbodying agents.

Fats are generally triglycerides of C₁₈-C₂₄ fatty acids andpredominantly C₁₈-C₁₉ fatty acids with melting points or melting pointranges of between about 28° C. and about 45° C. Hard fats in the form ofsemisynthetic fats for the production of suppositories consist of amixture of mono-, di- and triglycerides of saturated C₁₀-C₁₈ fattyacids. It is also possible to use paraffin fats, i.e. paraffins withmelting points or melting point ranges in the ranges-mentioned. Fats arethe actual excipient.

Oils are generally medium-chain triglycerides of C₈-C₁₆ fatty acids andpre-dominantly C₈-C₁₂ fatty acids which are liquid at room temperatureand have melting points or melting point ranges of between 0° C. and 20°C. and preferably of about 0° C. to 10° C. It is also possible to useparaffin oils, i.e. paraffins with melting points or melting pointranges in the ranges mentioned. Oils are used principally as solvents orsolubilizers, as suspension aids or as emulsifiers.

Such fats and/or oils can be obtained for example from plant rawmaterials such as coconuts, palm kernels, olives or rape-seed, or fromanimal raw materials such as tallow, lard or blubber, and may behydrogenated.

The weight ratio of the pharmaceutical active substance to the excipientis preferably 5% to 15%, particularly preferably 7% to 12% and veryparticularly preferably about 8.5% to 9.5%, based on the total weight ofthe excipient. The pharmaceutically active dose for adults is generallyin the range from 150 mg to 250 mg per capsule and averages about 200mg, corresponding to an average dose of about 3 mg/kg body weight.

The consistency of the preparation according to the invention is notcritical as it has practically no influence on the stability of theactive substance. The preparation can have a solid, pasty or liquidconsistency. The decisive factor governing the choice of the weightratio of the active substance to the excipient and the selection of thevarious components of the excipient is the industrial processability ofthe preparation in the capsule filling process. Also, the suspensionmust not throw a deposit during filling, i.e. it is necessary to assurethe uniformity of content of the preparation in the capsule during andafter filling. For this purpose the flowability of the preparation,which is normally in the form of a suspension, is adjusted so that thepreparation flows well during processing but takes the form of a pasteor solidifies after processing, in the filled state in the capsule. Thisis achieved by processing the preparation under pressure and/or aslightly elevated temperature in the filling process. It is alsopossible to incorporate additives into the preparation to facilitatesaid processing, examples being finely divided (disperse/highlydisperse) aluminium oxide or disperse/highly disperse silicon oxide.Such a consistency is easy to produce and presents no problems for thoseskilled in the art.

The quality and nature of the capsules used correspond to thecommercially available qualities known per se. The production of thesoft gelatin capsules preferred according to the invention is describede.g. in Pharmazeutische Technologie (Pharmaceutical Technology), H.Sucker, P. Fuchs, P. Speiser, Stuttgart 1991, pages 337-347.

The purpose of the capsule coating is to improve the lubrication of therectal form and ensure that it is easy to insert into the body. Suchlubricating coatings are known per se. Examples of coating materialsknown per se for rectal capsules are polyethylene glycols with averagemolecular weights of about 1550 and 20,000, glycerol monooleate andglycerol dioleate, polyvinyl acetate and talcum. Thus a compositionknown per se consists for example of 40.5 parts of polyethylene glycolwith an average molecular weight of about 20,000, 17.4 parts ofpolyethylene glycol with an average molecular weight of about 1550, 26.0parts of glycerol monooleate and glycerol dioleate (mixture), 1.2 partsof polyvinyl acetate and 14.9 parts of talcum. Capsule coatings aredescribed for example in Pharmazeutische Technologie (PharmaceuticalTechnology), H. Sucker, P. Fuchs, P. Speiser, Stuttgart 1991, page 343.

The preparation according to the invention can be manufactured forexample by mixing the excipients, e.g. the hard fat, at the meltingpoint in a suspension processing unit capable of being heated andevacuated. Other excipients, for example medium-chain triglycerides, andthe active substance are then added to the melt, after which the melt isprocessed to a homogeneous mass. The molten suspension obtained is thenfiltered through a sieve, after which the filtrate is degassed by theapplication of a vacuum and filled into capsules. The capsules obtainedin this way are provided with a coating in a manner known per se. It isalso possible to choose a different procedure, which creates no problemsper se for those skilled in the art.

The Examples below illustrate the invention.

EXAMPLE 1 Preparation of a Composition According to the Invention

30.6 kg of hard fat are melted at 45° C. in a stainless steel suspensionprocessing unit capable of being heated and evacuated, which has abuilt-in stirrer, homogenizer and forced circulation system(Diessel-Werke). 44.4 kg of medium-chain triglycerides are thenincorporated, with stirring, followed by 7.5 kg of artesunate. The massis then homogenized for 10 minutes under forced circulation. Thesuspension is then kept at 40° C.±2° C., with moderate stirring, andpassed through a sieve of mesh size 400 μm. The filtered suspension isdegassed for 2 to 3 hours by the application of a vacuum (residualpressure 0.5 to 0.2 bar absolute). The mixture obtained is filled intosoft gelatin capsules as described in Example 10. The batch issufficient for 150,000 capsules containing 50 mg.

EXAMPLES 2-8

The Examples listed in Table 1 were prepared analogously to Example 1.

TABLE 1 Medium-chain Example Artesunate Hard fat triglyceride no. mg mgmg Additives 2 200 40 350 — 3 200 20 570 — 4 50 32 359 — 5 50 4 387 — 6400 15 175 — 7 200 21 369 groundnut oil, 35 mg stearic acid, 10 mgAerosil, 3 mg 8 200 21 369 —

EXAMPLE 9 Comparative Example

25.2 kg of hard fat are melted at 45° C. in a stainless steel suspensionprocessing unit capable of being heated and evacuated, which has abuilt-in stirrer, homogenizer and forced circulation system(Diessel-Werke). 37.8 kg of medium-chain triglycerides, 0.75 kg of soyalecithin and 12.75 kg of polyoxyethylene glycol triricinoleate are thenadded, the mixture is homogenized and 7.5 kg of artesunate are added.The mass is then homogenized for 10 minutes under force circulation. Thesuspension is kept at 40° C.±2° C., with moderate stirring, and thenpassed through a sieve (mesh size 400 μm). The filtered suspension isdegassed for 2 to 3 hours by the application of a vacuum (residualpressure 0.5 to 0.2 bar absolute). The mixture obtained is filled intosoft gelatin capsules as described in Example 10. The batch issufficient for 150,000 capsules containing 50 mg.

EXAMPLE 10 Production of Soft Gelatin Capsules

(a) 46 kg of gelatin, 19.8 kg of glycerol (85%) and 34.2 kg of purifiedwater are introduced into a separated, heatable stainless steel tankequipped with a stirrer (Diessel). The mass is melted at 70° C. to givea clear melt. Gas bubbles are removed by stirring slowly. A suspensionof 1.26 kg of titanium dioxide in glycerol (85%) (1 part of titaniumdioxide to 1 part of 85% glycerol) and 0.14 kg of yellow iron oxide in85% glycerol (1:2), in 0.7 kg of purified water, is added to the meltand the mixture is stirred until the distribution is homogeneous. Thismixture is used for several batches of capsules.

(b) The mass prepared as described in section (a) is introduced into anencapsulating machine, with cooling, and used encapsulate a compositionaccording to Examples 1-8 by the rotary die process of R. P. Scherer.The capsules are predried in a rotary dryer (Scherer system) until theyare sufficiently firm. The capsules are then dried further on trays, theincoming air being at a temperature of 15 to 26° C. at a relativehumidity of 10-40%. When drying is complete, defective capsules arediscarded.

(c) A perforated coating drum (Glatt GC) is used to provide the capsuleswith the lubricating coating. The lacquer formulation is sprayed onunder forced air circulation until the requisite amount per capsule hasbeen applied. Each batch of coating material is obtained by dissolvingor suspending 0.6675 kg of polyethylene glycol with an average molecularweight of 20,000, 0.2865 kg of polyethylene glycol with an averagemolecular weight of 1550, 0.429 kg of glycerol monooleate and dioleate(mixture), 0.0195 kg of polyvinyl acetate and 0.2475 kg of talcum in anethanol/water mixture. The coated capsules are dried and inspected,defective capsules being discarded. The capsules are then sealed intoPVDC/aluminium blister packs.

Stability Testing of the Preparations

The compositions prepared as described in Examples 1-8 and ComparativeExample 9 above, filled into rectal capsules (produced as described inExample 10), were subjected to a stability test under the followingstorage conditions:

1. conditions at room temperature: 20-25° C.,

relative humidity: 60%, storage period: 6 to 24 months

2. in the drying cabinet:

(i) 31° C., relative humidity: 75%, storage period: 6-24 months

(ii) 40° C., relative humidity: 75%, storage period: 6-24 months

(iii) 41° C., relative humidity: 75%, storage period: 6-24 months

After storage, the following aspects were examined: the appearance ofthe preparation (discoloration etc.), the average weight (nominal value:894 mg±10%), the filling weight, the disintegration time in water at 37°C., and the content of artesunate and, as degradation products,dihydroartemisinin (artesol) and artemisinin. It was found that a highdegree of instability of the comparative preparation of Example 9occurred after only a short time (i.e. after 3 months at 40° C. and 75%relative humidity and after 6 months at 31° C. and 75% relativehumidity), so the experiments were not continued. After 3 months at 40°C. and 75% relative humidity, the content of artesunate dropped to86.6%. Artesol (6%) and artemisinin (2.2%) were found as by-products.The analysis results obtained after 6 months at 31° C. and 75% relativehumidity were analogous.

By contrast, the preparations of Examples 1-8 were found to have anexcellent stability. At room temperature (20-25° C.) and a relativehumidity of 60%, the content of artesol and artemisinin was unmeasurableafter 13 months. The content of artesunate remained unchanged at 102.3%.

After storage for 13 months in a drying cabinet at 31° C. and a relativehumidity of 75%, analysis showed the following values: artesol: 0.5%,artemisinin: unmeasurable, artesunate: 100.3%.

After storage for 13 months in a drying cabinet at 40° C. and a relativehumidity of 75%, analysis showed the following values: artesol: 2.0%,artemisinin: unmeasurable, artesunate: 89.5%.

These results confirm that the stability of the composition according tothe invention is 3 years at room temperature.

What is claimed is:
 1. A pharmaceutical composition in the form forrectal administration active against malaria parasites andmultiresistant lines of Plasmodium falciparum, comprising apharmaceutically effective amount of an active substance selected fromthe group consisting of artemisinin, derivatives of artemisinin andcombinations thereof, and an excipient which is inert towards the activesubstance, and which excipient is substantially free of compounds withan HLB value in the range of about 7 to about 9.9.
 2. The compositionaccording to claim 1, wherein said artemisinin derivative is selectedfrom the group consisting of artemether, artemisin and/or artesunate,and combinations thereof.
 3. The composition according to claim 1,wherein any compound with an HLB value of 7-9.9 is present in thecomposition in an amount of at most 10 percent by weight of the totalcomposition.
 4. The composition according to claim 1, wherein anycompound with an HLB value of 7-9.9 is present in the composition in anamount of at most 5 percent by weight of the total composition.
 5. Thecomposition according to claim 1, wherein any compound with an HLB valueof 7-9.9 is present in the composition in an amount of at most 2 percentby weight of the total composition.
 6. The composition according toclaim 1, wherein no compound with an HLB value of 7-9.9 is detectable inthe composition.
 7. The composition according to claim 1, wherein theconcentration of compounds with an HLB value in the ranges of 4-6.9 and10-13 is at most 10 percent by weight, based on the weight of the activesubstance, and wherein no compound with an HLB value in the ranges of4-6.9 and 10-13 is detectable in the composition.
 8. The compositionaccording to claim 1, wherein the concentration of compounds with an HLBvalue in the ranges of 4-6.9 and 10-13 is at most 5 percent by weight,based on the weight of the active substance, and wherein no compoundwith an HLB value in the ranges of 4-6.9 and 10-13 is detectable in thecomposition.
 9. The composition according to claim 1, wherein theconcentration of compounds with an HLB value in the ranges of 4-6.9 and10-13 is at most 2 percent by weight, based on the weight of the activesubstance, and wherein no compound with an HLB value in the ranges of4-6.9 and 10-13 is detectable in the composition.
 10. The compositionaccording to claim 1, wherein the concentration of compounds with an HLBvalue in the range of 13.1-15 is at most 10 percent by weight, based onthe weight of the active substance, and wherein no compound with an HLBvalue in the range of 13.1-1 is detectable in the composition.
 11. Thecomposition according to claim 1, wherein the concentration of compoundswith an HLB value in the range of 13.1-15 is at most 5 percent byweight, based on the weight of the active substance, and wherein nocompound with an HLB value in the range of 13.1-1 is detectable in thecomposition.
 12. The composition according to claim 1, wherein theconcentration of compounds with an HLB value in the range of 13.1-15 isat most 2 percent by weight, based on the weight of the activesubstance, and wherein no compound with an HLB value in the range of13.1-1 is detectable in the composition.
 13. The composition accordingto claim 1, wherein said excipient may be selected from the groupconsisting of waxes, fats, and oils, and combinations thereof, andwherein said waxes, fats, and oils are of vegetable or animal origin.14. The composition according to claim 1, wherein said excipient may beselected from the group consisting of paraffin waxes, paraffin oils, andcombinations thereof.
 15. The composition according to claim 1, whereinthe weight ratio of said active substance to said excipient is 5% to15%.
 16. The composition according to claim 1, wherein said compositionis in the form of suppositories, rectal foams, enemas, or rectalcapsules.
 17. The composition according to claim 16, wherein saidsuppositories comprise a soft gelatin capsule containing apharmaceutically active substance in a pharmaceutically effectiveamount.
 18. The composition of claim 17, wherein said soft gelatincapsule is provided with a lubricating coating.
 19. A method ofcontrolling malaria parasites and multiresistant lines of Plasmodiumfalciparum by administering rectally to a patient the composition ofclaim 1.